Genetics 2 Flashcards
genetic linkage and morgans experiment
Genetic linkage describes the way in which two genes that are located close to each other on a chromosome are often inherited together. … In fact, the closer two genes are to one another on a chromosome, the greater their chances are of being inherited together or linked.
Morgan took flies that were homozygous dominant for both traits, and bred them with flies that were recessive for both traits.
The gametes produced by the male must contain the recessive allele for each trait.
If the genes that control these traits are on separate chromosomes, we would expect the law of independent assortment to hold true, and each of these four results would be equally probable, resulting in about 25% of each genotype in the F2 generation.
Instead, if the genes were on the same chromosome, the alleles may not separate.
The experimental result showed something in between.
He concluded that the two genes were on the same chromosome, but that some process must separate the two genes.
genetics maps and alfred sturtevent
Alfred sturtevent worked on a genetic map, meant to elucidate the specific loci of genes within a chromosome.
More DNA between genes means it is more likely that crossing over will occur between them.
Thus resulting in recombination with respect to those genes.
The likelihood of recombination for two genes is called recombination frequency.
Hence, by looking at recombination frequencies between genes, he was able to calculate how far apart different genes are on a chromosome.
He used recombination frequencies to calculate the distance between two genes.
females x chromosome barr body
Females deactivate/render transcriptionally silent, one of their X chromosomes.They highly condense it. As result, males and females have an equal dosage of X linked genes, represented on a single active X chromosome. However, it is still transmissible to gametes. Carrier females who do not have the mutation, usually do not express the phenotype, however different X chromosomes may be expressed in different cells throughout the body, and as a result, you may get varying levels of clinical expression.
Since women have 2 X chromosomes, they have 2 chances to get the normal allele, and hence their chances of getting the mutation are low.
association between markers and genetic traits
Association can occur between neighbouring markers and the trait, not just the causative mutation itself. However association between the neighbouring marker and the trait will decline as a result of a number of factors;
Association will decline with;
Time since the mutation occurred on a specific genetic background
The distance between the marker and the causative variant.
If the influence of the variant on the trait is weak or swamped by other factors.
If the mutation in the gene which causes the trait is one of a number of mutations of similar effect.
cystic fibrosis
This is a genetic disease which has its world maximum prevalence in
Ireland with 1/1800 births. It is recessive and involves chronic bacterial infection,
inflammation of the lungs and high electrolyte level in sweat.
The gene, which was unknown was known to influence chloride ion transport and
mucus consistency on epithelial surfaces. This was the first gene identified through
linkage analysis.
cystic fibrosis symptoms
•Very salty-tasting skin
•Persistent coughing, at times with phlegm;
•Frequent lung infections;
•Wheezing or shortness of breath;
•Poor growth/weight gain in spite of a good appetite;
1950s: Few children with CF lived to attend primary school.
Today: Many people with the disease in Ireland can now expect to live into
their 30s, 40s and beyond.
genetic linkage and cystic fibrosis
We first cut the DNA with a restriction enzyme, eg Taql
Fragment size separation by gel electrophoresis
Fragment size is determined by whether it is cut/not cut by the restriction enzyme
Visualisation of the polymorphism as a particular gene by radioactive probing with specific marker DNA
Used southern blotting
First, linkage analysis using markers spread around the genome in many nuclear family pedigrees gave a region on chromosome 7 which was linked to the gene. This was bounded by recombinations with two markers: MET and D7S8
First, linkage analysis using markers spread around the genome in many nuclear family pedigrees gave a region on chromosome 7 which was linked to the gene. This was bounded by recombinations with two markers: MET and D7S8
3 RFLPs which showed strongest association, all within new cystic fibrosis transmembrane conductance regulator (CFTR) gene, close to a 3bp deletion.
Describe the mutation associated with cystic fibrosis
Using northern blotting, we can see there is a deletion of codon for F
We detect the mutation, called the delta F308 mutation using oligo hybridisation.
Having two copies of the mutant gene, the protein product will produce a CFTR protein that has dysfunctional transmembrane transport of ions.
CFTR is important in the regulation of fluid flow within cells, and affects the components of sweat, digestive fluids and mucus.
68% of all chromosomes with a copy of the gene causing the disease show this same 3bp deletion.
Natural selection and cystic fibrosis
There is some evidence from the gene products involvements in ion transport and water retention, that it may have been subject to natural selection in the past, with heterozygote advantage causing high incidence of the disease alles
Possibly resistance to typhoid, as cells expressing wild type CFTR internalise more of the typhoid bacteria (S.typhi) than those with two copies of the common mutant.
Gene therapy for CF
Take a viral vector that will affect numerous cell types.
Into the genome, we package the normal CFTR gene.
Ivacaftor
A new agent, Ivacaftor was approved by the US food and Drug administration.
A CFTR potentiator. The protein is trafficked to the correct area.
It works for the G551D mutation in which the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel.
Ivacaftor improves the transport of chloride through the chloride ion channel by binding to the channels directly, to induce a non-conventional mode of gating, which in turn increases the probability that the channel is open.
Example of homozygous individuals expressing autosomal recessive disorder traits
While carriers of an autosomal recessive disorder are asymptomatic, they can sometimes express some disease related traits.
EG sickle cell disease; individuals homozygous for beta globin mutation produce abnormal hemoglobin.
Carriers produce mutant beta-globin, that is codominantly expressed with the normal beta-globin and heterozygotes have mild anemia.
Under severe hypoxic stress, exhaustion/infection/high altitudes, individuals can develop complications of sickle cell disease.
So while sickle cell disease is recessively inherited, the sickle cell trait can sometimes act as a dominant trait.
locud heterogeneity
Occurs when both parents who are affected with the same common recessive disorder produce multiple unaffected children.
Somatic mutations - the journey from a single celled zygote to an adult human involves about 10^4 mitotic cell divisions.
Mutation is unavoidable, generally a small number of cells
This mutation can give rise to descendant cells that act abnormally
Glioblastoma multiforme
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How do restriction enzymes work in gene mapping
They recognize specific DNA sequences, and will not cut if these are mutated.
There are many, thousands of single base pair polymorphisms in the human genome which may be assayed by the cutting/not cutting of enzymes at particular sites.
They are then visualized using a technique called southern blotting
